In a Cochrane review «Kreijkamp-Kaspers S, Hawke K, Guo L ym. Oral antif...»1, the pooled analyses included 43 studies with 9730 participants. All studies were RCTs, and 16 had a placebo arm. Twenty-six were published 2000 or earlier. Participants with toenail onychomycosis confirmed by at least one positive culture or confirmed fungal elements on direct microscopy or histological examination of the nail. The average age of the participants across studies ranged from 36 to 68 years, and most studies included participants aged 18 and over, with only three studies accepting participants aged 14 to 16 years. The participants mainly had subungual fungal infection of the toenails.
Seventeen studies (1317 participants) compared azole with terbinafine. Azoles included fluconazole «Havu V, Heikkilä H, Kuokkanen K ym. A double-blind...»2; posaconazole «Elewski B, Pollak R, Ashton S ym. A randomized, pl...»3; fluconazole and itraconazole in two arms «Arca E, Tastan HB, Akar A ym. An open, randomized,...»4; and itraconazole, ketoconazole and fluconazole in three arms «Gupta AK, Gregurek-Novak T. Efficacy of itraconazo...»5. All other studies used itraconazole as the only azole. Fifteen studies reported clinical cure as an outcome. In the pooled azole group, 521 (46 %) participants achieved clinical cure compared to 598 (58 %) participants in the combined terbinafine group. There was moderate-quality evidence that participants in the azole group were 18 % less likely to achieve clinical cure compared to participants receiving terbinafine (RR 0.82, 95 % CI 0.72 to 0.95, 15 studies, 2168 participants; I² = 62 %). Two studies caused statistical heterogeneity «Havu V, Heikkilä H, Kuokkanen K ym. A double-blind...»2, «Sigurgeirsson B, Billstein S, Rantanen T ym. L.I.O...»6, and removing them from the analyses reduced the statistical heterogeneity to 0 %. This did not change the direction of the effect but did reduce its magnitude (RR 0.89, 95 % CI 0.82 to 0.97). The authors could not explain the statistical heterogeneity based on clinical differences between these studies and the rest of the studies, and it was suspected the outlier effect is due to the size of studies «Havu V, Heikkilä H, Kuokkanen K ym. A double-blind...»2, «Sigurgeirsson B, Billstein S, Rantanen T ym. L.I.O...»6.
When comparing subgroups based on short- or long-term follow-up, low statistical heterogeneity was observed (I² = 3.3 %, P value for subgroup differences = 0.55). In studies with short-term follow-up, the azole group was 14 % less likely to achieve clinical cure (RR 0.86, 95 % CI 0.77 to 0.96), and with long-term follow-up the azole group was 20 % less likely to achieve clinical cure (RR 0.80, 95 % CI 0.63 to 1.00) compared to the terbinafine group. However, this difference was not statistically significant.
Seventeen studies reported mycological cure as an outcome. In the pooled azole group, 685 (52 %) participants achieved mycological cure, compared to 831 (68 %) participants in the pooled terbinafine group. There was moderate-quality evidence that participants in the azole group were 23 % less likely to achieve mycological cure compared to participants receiving terbinafine (RR 0.77, 95 % CI 0.68 to 0.88, 17 studies, 2544 participants) (I² = 73 %). When only including studies using the azole itraconazole the effect estimate remained similar (RR 0.78, 95 % CI 0.67 to 0.90).
Comment: The level of evidence is downgraded by the unclear risk of bias in original trials.